This invention relates to new antibacterial substances and processes for their preparation. More particularly, it is concerned with novel 3-cephem compounds containing a 3-vinyl group, and with intermediates and processes useful in their preparation.
In the past several decades, various antibiotic substances have proven to be invaluable in treatment and control of various infections. However, new antibiotics are constantly being sought in order to supplement and expand the physicians armamentarium, particularly for the treatment of infections involving pathogens which have become resistant to the chemotherapeutic agents now in use.
Prior Art of Interest
German Offenlegungsschrift No. 2,103,014.
Summary of the Invention
It is therefore an object of this invention to provide novel antibiotic substances and processes for their synthesis. Another object is to provide processes and intermediates useful in the synthesis of the novel antibiotics. Other objects will be apparent from the detailed description hereinafter provided.
The novel 3-vinyl compounds of this invention can be represented by the structural formula ##STR1## wherein
R.sub.4 represents an acyl group, preferably a carboxylic acid acyl group that is conventionally employed in the penicillin and cephalosporin art;
B is hydrogen or methoxy;
wherein when B is methoxy:
R.sub.2 and R.sub.3 may be the same or different and are each selected from the following:
(a) hydrogen;
(b) aryl (eg. phenyl, styryl, benzyl, phenethyl, trityl, cinnamyl, mesityl, tolyl, cumenyl, xylyl including substituted aryl hydrocarbons wherein the substituents may be ##STR2## halo, hydroxyl, NH.sub.2 ; etc.;
(c) heterocyclic aromatic, particularly a 5 or 6 membered heterocyclic group containing at least one hetero atom selected from S, N and O, eg. thienyl, thiazolyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrolidenyl, oxyazoloyl, 1,2,3-thiadiazolyl, 1-oxidopyridyl, tetrahydropyranzoyl, furazanoyl including substituted heterocyclic aromatic moieties wherein the substituents may be halo (eg. chloro, fluoro, bromo); lower alkyl of 1-6 cabon atoms (eg. methyl, ethyl, propyl, pentyl, hexyl,); trifluoromethyl; mono- and di-lower alkyl substituted sulfamyl (eg. dimethylsulfamyl, methylsulfamyl); nitro; lower alkoxy or 1-6 carbon atoms (methoxy, ethoxy, pentoxy, etc..); also included within the scope of heterocyclic aromatic are the substituted and unsubstituted fused ring hetero moieties such as quinoline, isoquinoline etc..;
(d) Alkyl, preferably lower alkyl of 1-6 carbon atoms such as methyl, ethyl, propyl, t-butyl, hexyl; including substituted alkyl wherein the substitutents may be halo (e.g. chloro, fluoro or bromo such as CF.sub.3), hydroxyl, NH.sub.2, NO.sub.2, etc..;
(e) cycloaliphatic, preferably monocyclic hydrocarbons of 3-6 carbon atoms (eg. cyclopropyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclopentadienyl etc..); ##STR3## wherein R'.sub.4 and R'.sub.5 are selected from hydrogen, lower alkyl of 1-6 carbon atoms and aryl (e.g. phenyl, styryl, benzyl, phenylethyl, tolyl, etc..), including aryl groups which may be substituted by halo (chloro, bromo, fluoro); --OH, amino, trifluoromethyl, alkyl of 1-6 carbon atoms and the like;
(1) heterocyclic aliphatic, particularly a 5 or 6 membered heterocyclic aliphatic group containing at least one atom selected from O, N and S (e.g. ##STR4##
(n) alkanoyloxyalkyl wherein the alkanoyl moiety is straight or branched and has 1-6 carbon atoms and the alkyl portion has 1-6 carbon atoms such as acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, propionyloxyethyl, acetoxypropyl, etc.
wherein when B is hydrogen:
R.sub.2 and R.sub.3 may be the same or different and are each selected from the following:
(a) heterocyclic aromatic, particularly a 5 or 6 membered heterocyclic group containing at least one hetero atom selected from S, N and O, e.g. thienyl, thiazolyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, furazanyl including substituted heterocyclic aromatic wherein the substituents may be halo (e.g. chloro, fluoro, bromo); lower alkyl of 1-6 carbon atoms (e.g. methyl, ethyl, propyl, pentyl, hexyl); trifluoromethyl; mono- and di-lower alkyl substituted sulfamyl (eg. dimethylsulfamyl, methylsulfamyl), nitro; lower alkoxy of 1-6 carbon atoms (methoxy, ethoxy, pentoxy etc.); also included within the scope of heterocyclic aromatic are the substituted and unsubstituted fused ring hetero moieties such as quinoline, isoquinoline, etc..; ##STR5##
wherein R'.sub.4 and R'.sub.5 are the same or different and are selected from hydrogen lower alkyl of 1-6 carbon atoms and aryl (eg. phenyl, sytryl, benzyl, phenylethyl, tolyl etc. including aryl groups which may be substituted by halo (chloro, bromo, fluoro); --OH; amino; trifluoromethyl; alkyl of 1-6 carbon atoms and the like.
(e) heterocyclic aliphatic group, particularly a 5 or 6 membered heterocyclic aliphatic group containing at least one atom selected from O, N and S (eg. ##STR6##
(f) NO.sub.2 --.
(g) alkanoyloxyalkyl wherein the alkanoyl moiety is straight or branched and has 1-6 carbon atoms and the alkyl portion has 1-6 carbon atoms such as acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, propionyloxyethyl, acetoxypropyl, etc.
(h) hydrogen with the proviso that both R.sub.2 and R.sub.3 may not be hydrogen.
The acyl radical represented by R.sub.4 can be a substituted or unsubstituted aliphatic, aromatic or heterocyclic, araliphatic or heterocyclyaliphatic carboxylic acid radical or a carbothioic acid radical such as the acyl radicals of the known cephalosporins and penicillins. These acyl radicals can be represented by the general formula ##STR7## where R.sub.y is a radical of the group defined below, m and n represent 0-4 and R.sub.x represents R" or ZR", which are defined below.
The following compilation of acyl groups illustrated below are merely representative and not intended to be exhaustive.
One group of acyl radicals can be represented by the acyl group general formula: ##STR8## wherein R" represents a substituted or unsubstituted straight or branched chain alkyl, alkenyl or alkynyl group; aryl, aralkyl; cycloalkyl; or a heteroaryl or heteroaralkyl group. These groups can be unsubstituted or can be substituted by radicals such as alkyl, akoxy, halo, cyano, carboxy, sulfoamino, carbamoyl, sulfonyl, azido, amino, substituted amino, haloalkyl, carboxyalkyl, carbamoylalkyl, N-substituted carbamoylalkyl, guanidino, N-substituted guanidino, quanidinoalkyl, and the like. Representative examples of such acyl groups that might be mentioned are those wherein R" is benzyl, p-hydroxybenzyl, 4-amino-4-carboxybutyl, methyl, cyanomethyl, 2-pentenyl, n-amyl, n-heptyl, ethyl, 3- or 4-nitrobenzyl, phenethyl, .beta.,.beta.-diphenylethyl, methyldiphenylmethyl, triphenylmethyl, 2-methoxyphenyl, 2,6-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,5-dimethyl-4-isozazolyl, 3-butyl-5-methyl-4-isoxazolyl, 5-methyl-3-phenyl-4-isoxazolyl, 3-(2-chlorophenyl)-5-methyl-4-isoxazolyl, 3-(2-dichlorophenyl)-5-methyl-4-isoxazolyl, D-4-amino-4-carboxybutyl, D-4-N-benzoylamino-4-carboxy-n-butyl, p-aminobenzyl, o-aminobenzyl, m-aminobenzyl, (3-pyridyl)methyl, 2-ethoxy-1-naphthyl, 3-carboxy-2-quinoxalinyl, 3-(2,6-dichlorophenyl)-5-(2-furyl)-4-isoxazolyl, 3-phenyl-4-isoxazolyl, 5-methyl-3-(4-guanidinophenyl)-4-isoxazolyl, 4-guanidinomethylphenyl, 4-guanidinomethylbenzyl, 4-guanidinobenzyl, 4-guanidinophenyl, 2,6-dimethoxy-4-guanidinophenyl, o-sulfobenzyl, p-carboxymethylbenzyl, p-carbamoylmethylbenzyl, m-fluorobenzyl, m-bromobenzyl, p-chlorobenzyl, p-methoxybenzyl, 1-naphthylmethyl, 3-isothiazolylmethyl, 4-isothiazolylmethyl, 5-isothiazolylmethyl, 4-pyridylmethyl, 5-isoxazolylmethyl, 4-methoxy-5-isoxazolylmethyl, 4-methyl-5-isoxazolylmethyl, 1-imidazolylmethyl, 2-benzofuranylmethyl, 2-indolylmethyl, 2-phenylvinyl, 2-phenylethynyl, 2-(5-nitrofuranyl)vinyl, phenyl, o-methoxyphenyl, o-chlorophenyl, o-phenylphenyl, p-aminomethylbenzyl, 1-(5-cyanotriazolyl)methyl, difluoromethyl, dichloromethyl, dibromomethyl, 1-(3-methylimidazolyl)methyl, 2- or 3-(5-carboxymethylthienyl)methyl, 2- or 3-(4-carbamoylthienyl) methyl, 2- or 3-(5-methylthienyl)methyl, 2- or 3-(5-methoxythienyl)methyl, 2- or 3-(4-chlorothienyl)methyl, 2- or 3-(5-sulfothienyl)methyl, 2- or 3-(5-carboxythienyl)methyl, 3-(1,2,5-thiadiazolyl)methyl, 3-(4-methoxy-1,2,5-thiadiazolyl)methyl, 2-furylmethyl, 2-(5-nitrofuryl)methyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, and tetrazolylmethyl.
The acyl group can also be a radical of the formula ##STR9## wherein n is 0-4, Z represents oxygen or sulfur, and R" is defined as above. Representative members of the substituent EQU --(CH.sub.2).sub.n ZR"
that might be mentioned are allylthiomethyl, phenylthiomethyl, butylmercaptomethyl, .alpha.-chlorocrotylmercaptomethyl, phenoxymethyl, phenoxyethyl, phenoxybutyl, phenoxybenzyl, diphenoxymethyl, dimethylmethoxymethyl, dimethylbutoxymethyl, dimethylphenoxymethyl, 4-guanidinophenoxymethyl, 4-pyridylthiomethyl, p-(carboxymethyl)phenoxymethyl, p-(carboxymethyl)phenylthiomethyl, 2-thiazolylthiomethyl, p-(sulfo)phenoxymethyl, p-(sulfo)phenylthiomethyl, p-(carboxy)phenoxymethyl, p-(carboxy)phenylthiomethyl, p-(carboxymethyl)phenoxymethyl, p-(carboxymethyl)phenylthiomethyl, 2-pyrimidinylthiomethyl, phenylthiomethyl, 1-(5,6,7,8-tetrahydronaphthyl)oxomethyl, 6,8-bis(methylthio)octanoyl.
Alternatively, the acyl group can be a radical of the formula ##STR10## wherein R" is defined as above and R"' is a radical such as amino, hydroxy, azido, carbamoyl, guanidino, acyloxy, halo, sulfamino, tetrazolyl, sulfo, carboxy, carbalkoxy, and the like. Representative members of the substituent ##STR11## that might be mentioned are .alpha.-aminobenzyl, .alpha.-amino-2-thenyl, .alpha.-methylaminobenzyl, .alpha.-amino-.gamma.-methylmercaptopropyl, .alpha.-amino-3 or 4-chlorobenzyl, .alpha.-amino-3 or 4-hydroxybenzyl, .alpha.-amino-2,4-dichlorobenzyl, .alpha.-amino-3,4-dichlorobenzyl, D(-)-.alpha.-hydroxybenzyl, .alpha.-carboxybenzyl, .alpha.-amino-3-thenyl, .alpha.-amino-2-thenyl, D(-)-.alpha.-amino-3-chloro-4-hydroxybenzyl, D(-)-.alpha.-amino-3-thenyl, 1-aminocyclohexyl, .alpha.-(5-tetrazolyl)benzyl, .alpha.-sulfaminobenzyl, .alpha.-sulfamino-3-thenyl, .alpha.-(N-methylsulfamino)-benzyl, D(-)-.alpha.-guanidino-2-thenyl, D(-)-.alpha.-guanidionbenzyl, .alpha.-guanylureidobenzyl, .alpha.-hydroxybenzyl, .alpha.-azidobenzyl, .alpha.-fluorobenzyl, 4-(5-methoxy-1,3-oxadiazole)-aminomethyl, 4-(5-methoxy-1,3-oxadiazole)-hydroxymethyl, 4-(5-methoxy-1,3-oxadiazole)-carboxymethyl, 4-(5-methoxy-1,3-sulfadiazole)-aminomethyl, 4-(5-methoxy-1,3-sulfadiazole)-hydroxymethyl, 4-(5-methoxy-1,3-sulfadiazole)-carboxymethyl, 2-(5-chlorothienyl)-aminomethyl, 2-(5-chlorothienyl)-hydroxymethyl, 2-(5-chlorothienyl)-carboxymethyl, 3-(1,2-thiazole)-aminomethyl, 3-(1,2-thiazole)-hydroxymethyl, 3-(1,2-thiazole)-carboxymethyl, 2-(1,4-thiazolyl)-aminomethyl, 2-(1,4-thiazolyl)-hydroxymethyl, 2-(1,4-thiazolyl)-aminomethyl, 2-(1,4-thiazolyl)-hydroxymethyl, 2-(1,4-thiazoyly)-carboxymethyl, 2-benzothienylamino ethyl, 2-benzothienylhydroxymethyl, 2-benzothienylcarboxymethyl, 2-azidooctyl-3-phenyl-3-azidomethyl, .alpha.-sulfobenzyl, and .alpha.-phosphonobenzyl.
Alternatively, the group ##STR12## can be a sulfonamido group such as phenylsulfonamido, ethylsulfonamido, benzylsulfonamido, 2,5-dimethylsulfonamido, 4-chlorosulfonamido, 4-chlorophenylsulfonamido, 4-methoxysulfonamido, and the like.
The acyl substituents of the general formula EQU R.sub.11 R.sub.10 CHCO
wherein R.sub.10 and R.sub.11 are as defined below represent a preferred group of substituents because of their generally useful antibiotic activity. R.sub.10 represents hydrogen, halo, amino, guanidino, phosphono, hydroxy, tetrazolyl, carboxy, sulfo or sulfamino. R.sub.11 represents phenyl, substituted phenyl, a monocyclic heterocyclic 5- or 6-membered ring containing one or more oxygen, sulfur or nitrogen atoms in the ring, substituted heterocycles, phenylthio, heterocyclic or substituted heterocylcic thio groups; or cyano. The substituents can be halo, carboxymethyl, guanidino, guanidinomethyl, carboxamidomethyl, aminomethyl, nitro, methoxy or methyl. Examples of these preferred substituents that might be mentioned are phenacetyl, 3-bromophenylacetyl, p-aminomethylphenylacetyl, 4-carboxylmethylphenylacetyl, 4-carboxamidomethylphenylacetyl, 2-furylacetyl, 5-nitrofurylacetyl, 3-furylacetyl, 2-thienylacetyl, 5-chlorothienylacetyl, 5-methoxythienylacetyl, .alpha.-guanidino-2- thienylacetyl, 3-thienylacetyl, 4-methylthienylacetyl, 3-isothiazolylacetyl, 4-methoxyisothiazolylacetyl, 4-isothiazolylacetyl, 3-methylisothiazolylacetyl, 5-isothiazolylacetyl, 3-chloroisothiazolylacetyl, 3-methyl-1,2,5-oxidiazolylacetyl, 1,2,5-thiadiazolyl-4-acetyl, 3-methyl-1,2,5-thiadiazolyl-4-acetyl, 3-chloro-1,2,5-thiadiazolyl-4-acetyl, 3-methoxy-1,2,5-thiadiazolyl-4-acetyl, phenylthioacetyl, 4-pyridylthioacetyl, cyanoacetyl, tetrazolylacetyl, .alpha.-fluorophenylacetyl, D-phenylglycyl, 4-hydroxy-D-phenylglycyl, 2-thienylglycyl, 3-thienylglycyl, phenylmalonyl, 3-chlorophenylmalonyl, 2-thienylmalonyl, 3-thienylmalonyl, .alpha.-phosphonophenylacetyl, .alpha.-sulfaminophenylacetyl, .alpha.-hydroxyphenylacetyl, .alpha.-tetrazolylphenylacetyl and .alpha.-sulfophenylacetyl.
Pursuant to a preferred embodiment of this invention, R.sub.4 is represented by the formula ##STR13## wherein X is hydrogen, halogen, amino, guanidino, phosphono, hydroxy, tetrazolyl, carboxy, sulfo, or sulfamino; R.sub.t is phenyl, substituted phenyl, a monocyclic heterocyclic 5- or 6-membered ring containing one or more oxygen, sulfur or nitrogen atoms in the ring, substituted heterocycles, phenylthio, phenyloxy, heterocyclic or substituted heterocyclic thio groups, lower alkyl (1-6 carbon atoms), or cyano; the substituents on the R.sub.t group being halo, carboxymethyl, guanidino, guanidinomethyl, carboxamidomethyl, aminomethyl, nitro, methoxy or methyl. Particularly preferred are acyl groups where X is hydrogen, hydroxy, amino or carboxy and R.sub.t is phenyl, lower alkyl or a 5- or 6-membered heterocyclic ring having one or two sulfur, oxygen or nitrogen hetero atoms. Specific R.sub.2 substituents that might be mentioned as preferred include thiazolyl, thienyl, furyl and phenyl.
Also included within the scope of the invention are the non-toxic derivatives of the novel 3-vinyl cephem compounds. By the term "non-toxic" as applied to the compounds of the invention is meant those derivatives which are physiologically acceptable in the dosage at which they are administered. Such derivatives include salts and esters.
The cephalosporin compounds with which this invention is concerned are conveniently designated as "cepham" compounds containing the basic fused-ring betalactam thiazine structure ##STR14## which is known as cepham. Thus, the cephalosporin compounds are called "cephem" referring to the basic structure with a single olefin bond.
The novel 3-vinyl cephalosporin compounds of the invention may be prepared by reacting a phosphoranylidene compound of the formula ##STR15## with a carbonyl compound of the formula R.sub.2 --CO--R.sub.3 ;
wherein R.sub.4 is a carboxylic acyl group conventionally employed in the penicillin and cephalosporin art;
B is hydrogen or methoxy;
R may be the same or different organo group and includes alkyl, aralkyl or aryl groups or such groups substituted by, for example, one or more halogen atoms, nitro groups, cyano groups, amino groups, acyl groups, acylamido groups and the like. Examples of R groups of interest include the lower alkyl e.g. methyl, ethyl, propyl or butyl; and phenyl or substituted phenyl; and benzyl;
R.sub.6 is hydrogen or a carboxyl-blocking group;
and wherein R.sub.2 and R.sub.3 have the above defined meanings.
The carboxyl blocking group (R.sub.6) is, preferably, an ester formed with an alcohol or phenol which may readily be split off at a later stage of the reaction.
Generally, it is preferred to carry out the reaction with a cephalosporin compound wherein the carboxy group is blocked or protected since maximum yields of the desired product are obtained with such derivatives. It is preferable that a protecting group be utilized which can be removed to obtain the free acid without disruption of the .beta.-lactam moiety.
The group protecting the 4-carboxyl group may be formed with an alcohol (aliphatic or araliphatic), phenol, silanol, stannanol or acid which may readily be split off at a later stage of the reaction.
Suitable esters thus include compounds containing as the 4-ester group, a group selected from the following list which is representative and not intended to be an exhaustive list of possible ester groups:
(i)--COOCR.sup.a R.sup.b R.sup.c wherein at least one of R.sup.a, R.sup.b and R.sup.c is an electron-donor e.g. p-methoxyphenyl, 2,2,6-trimethylphenyl, 9-anthryl, methoxy, acetoxy, tetrahydrofur-2-yl, tetrahydropyran-2-yl or fur-2-yl. The remaining R.sup.a, R.sup.b and R.sup.c groups may be hydrogen or organic substituting groups. Suitable ester groups of this type include p-methoxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl.
(ii)--COOCR.sup.a R.sup.b R.sup.3 wherein at least one of R.sup.a, R.sup.b and R.sup.c is an electron-attracting group e.g. benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, arylsulphonylmethyl, 2-dimethylsulphoniumethyl, o-nitrophenyl or cyano. The remaining R.sup.a, R.sup.b and R.sup.c groups may be hydrogen or organic substituting groups. Suitable esters of this type include benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl.
(iii)--COOCR.sup.a R.sup.b R.sup.c wherein at least two of R.sup.a, R.sup.b and R.sup.c are hydrocarbon such as alkyl e.g. methyl or ethyl, or aryl e.g. phenyl and the remaining R.sup.a, R.sup.b and R.sup.c group, if there is one, is hydrogen. Suitable esters of this type include, t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl.
(iv)--COOR.sup.d wherein R.sup.d is adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl or tetrahydropyran-2-yl.
Silyl esters may conveniently be prepared from a halosilane or a silazane of the formula R.sup.4.sub.3 SiX; R.sup.4.sub.2 SiX.sub.2 ; R.sup.4.sub.3 Si.NR.sup.4.sub.2 ; R.sup.4.sub.3 SiR.sup.4.sub.3 ; R.sup.4.sub.3 Si.NH.COR.sup.4 ; R.sup.4.sub.3 Si.NH.CO.NH.SiR.sup.4.sub.3 ; R.sup.4 NH.CO.NR.sup.4.SiR.sup.4.sub.3 ; or R.sup.4 C(OSiR.sup.4.sub.3): NsiR.sup.4.sub.3 where X is a halogen and the various groups R.sup.4, which can be the same or different, represent hydrogen atoms or alkyl, e.g. methyl, ethyl, n-propyl, iso-propyl; aryl, e.g. phenyl; or aralkyl e.g. benzyl groups.
Preferred derivatives of silanols are silyl chlorides such as for example trimethylchlorosilane and dimethyldichlorosilane.
Protecting groups of particular interest include alcohols and phenols, and the like. R.sub.6 is preferably an alkyl or aralkyl group containing from 1 to 20 carbon atoms. Thus, R.sub.6 can be a lower alkyl group such as methyl, ethyl or tertiary butyl, a substituted alkyl such as phthalimidomethyl, succinimidomethyl, phenacyl, substituted phenacyl such as p-bromophenacyl, a .beta.-substituted ethyl group such as 2,2,2-trichloroethyl, 2-methylthioethyl or 2-(p-methylphenyl)-ethyl, an alkoxyalkyl group such as methoxymethyl, an aryloxyalkyl such as p-methoxyphenoxymethyl, an aralkyloxyalkyl group such as benzyloxymethyl, a substituted benzyl group such as p-nitrobenzyl, p-methoxybenzyl, 3,5-dinitrobenzyl, 2,4,6-trimethylbenzyl or 3,5-dichloro-4-hydroxybenzyl, benzhydryl or a substituted benzhydryl group such as p-methoxybenzhydryl, and the like. Preferred blocking groups are methyl, tertiary butyl, phenacyl, p-bromophenacyl, 2,2,2-trichloroethyl, p-methoxybenzyl, benzhydryl, methoxymethyl and p-methoxyphenoxymethyl.
The term "blocking group" as utilized herein is employed in the same manner and in accordance with the teaching of U.S. Pat. No. 3,697,515; the contents therein with respect to said blocking group being incorporated herein by reference.
The carboxyl groups may be regenerated from an ester by any of the usual methods; for example, acid- and base-catalysed hydrolysis (especially for silyl and stannyl esters) is generally applicable, as well as enzymicallycatalysed hydrolyses; however, aqueous mixtures may be poor solvents for these compounds and they may cause isomerizations, rearrangements, side-reactions, and general destruction, so that special methods may be desirable. Five suitable methods of deesterification are:
A--Reactions with Lewis acids: Suitable Lewis acids for reaction with the esters include trifluoroacetic acid, formic acid, hydrochloric acid in acetic acid, zinc bromide in benzene and aqueous solutions or suspensions of mercuric compounds. The reaction with the Lewis acid may be improved by addition of a nucleophile such as anisole.
B--Reduction: Suitable systems for effecting reduction are zinc/acetic acid, zinc/formic acid, zinc/lower alcohol, zinc/pyridine, palladised-charcoal and hydrogen, electrolysis, and sodium and liquid ammonia.
C--Attack by nucleophiles: Suitable nucleophiles are those containing a nucleophilic oxygen or sulphur atom for example alcohols, mercaptans and water.
D--Oxidative methods: For example, which involve the use of hydrogen perxoide and acetic acid.
E--Irradiation.
Of particular interest are the procedures involving cleavage of groups such as benzhydryl, tertiary butyl, p-bromophenacyl, p-methoxybenzyl and p-methoxyphenoxymethyl with an acid such as trifluoroacetic acid and cleavage of the 2,2,2-trichloroethyl and phenacyl groups by reaction with zinc and acetic acid.
In addition to blocking the carboxy group, it is generally preferred to block or protect any amino groups present in the starting materials since maximum yields of the desired products are obtained with such derivatives. For this purpose, the groups are preferably blocked with substituents that are readily removed. Such groups are well known in the art. For example, the amino group is most conveniently blocked by a group such as trichloroethoxycarbonyl, t-butoxycarbonyl, benzoylmethoxycarbonyl, trimethylsilyl, p-methoxybenzyloxy, o-nitrophenylthio, and the like.
The 3-phosphoranylidene starting materials, wherein B.dbd.H, are known and may be prepared in accordance with the teachings of German Offenlegungsschrift No. 2,103,014 which relate to the preparation of vinylcephalosporins as follows: ##STR16## wherein X is halogen; ##STR17##